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Genomics in the Journals: Sep 5, 2013

NEW YORK (GenomeWeb News) – In this month's issue of Cancer Prevention Research, a German team outlined a strategy for detecting gene mutations implicated in colon cancer and pre-cancer, first in colon tissue samples and then using DNA found in stool samples.

The group started by doing a PCR-based analysis that used locked nucleic acids to block wild type DNA, before relying on a high-resolution melting analysis to track down new and known colon cancer-related mutations in the adenomatous polyposis coli, or APC, gene.

After verifying the veracity of the approach for finding APC mutations in 80 colon tissue samples from individuals with colorectal cancer, adenoma, serrated lesions, or normal colonic mucosa, the researchers went on to apply it to DNA from dozens of stool samples — an analysis that uncovered nearly all of the same APC alterations detected in tissue samples.

The method showed promise for picking up disease-related mutations in the KRAS gene, too, spurring enthusiasm about more routine detection of potentially risky changes to colon cancer-associated genes.

"By using our technique for examining a selection of genes that become mutated during the process of colon cancer formation, it is possible to detect the very first stage of colon cancer and even pre-cancers in a stool sample," senior author Bettina Scholtka, a nutritional toxicology researcher with Germany's University of Potsdam, said in a statement, adding that the approach should make it possible to prevent colon cancer cases via detection and removal of pre-cancerous lesions.

An mBio study suggests there are at least 320,000 yet undiscovered viruses capable of infecting mammals. An international team led by investigators at Columbia University's Center for Infection and Immunity and EcoHealth Alliance in New York extrapolated that figure based on the viral diversity found in Indian flying fox bats in Bangladesh.

Within nearly 1,900 urine, feces, throat swab, and roost urine samples collected from seemingly healthy bats over several years, the researchers used PCR-based methods to track down 55 viruses belonging to nine different families. These included 50 viruses not found previously.

Using a statistical approach known as the Chao2 estimator, they predicted that the Indian flying fox likely harbors a total of around 58 viruses from those nine viral families, which could theoretically be found by sampling around 5,500 more samples from the Bangladeshi bats.

A similar statistics-based prediction indicated that the nine viral families likely contain around 320,000 viruses capable of infecting mammals. Moreover, the team estimated that it would cost around $1.4 billion to find around 85 percent of these mammalian viruses and some $6.3 billion to more or less account for all of them.

"For decades, we've faced the threat of future pandemics without knowing how many viruses are lurking in the environment, in wildlife, waiting to emerge," co-corresponding author Peter Daszak, president of EcoHealth Alliance, wrote. "Finally we have a breakthrough — there aren't millions of unknown virus, just a few hundred thousand, and given the technology we have it's possible that in my lifetime, we'll know the identity of every unknown virus on the planet."

The University of Colorado's Tamim Shaikh and colleagues used exome sequencing as part of their effort to unearth a new X-linked form of an inborn error of metabolism associated with the vitamin B12 derivative cobalamin — work that they described in a study set to appear online in the American Journal of Human Genetics this week.

While mutations to a gene called MMACHC have been linked to problems in metabolizing cobalamin, which acts as a co-factor for other metabolic enzymes, not all individuals showing metabolic signs of inborn cobalamin metabolism errors carry MMACHC mutations.

To explore alternative genetic causes for such conditions, investigators did whole-exome sequencing on a male child with an X-linked form of defective cobalamin metabolism and both of his unaffected parents. When they sifted through these protein-coding sequences, they found a suspicious missense mutation in a gene called HCFC1, which codes for a transcriptional regulator.

Targeted sequencing of that gene in another 17 patients unearthed several more HCFC1 mutations in 13 of the individuals with X-linked cobalamin metabolism problems. In addition, the team's follow-up experiments hinted that HCFC1 likely influences the expression of the previously known cobalamin metabolism culprit MMACHC.

A Kyoto University and RIKEN-led team detected ties between histone demethylation and sex determination in a mouse model of mammalian sex development. As they reported in Science, the researchers focused on an enzyme called Jmjd1a, which demethylates lysine 9 of the histone H3 — also known as H3K9.

In the absence of the Jmjd1a coding gene, the investigators saw frequent male-to-female switches amongst mice that were genetically male. Through a series of expression and chromatin immunoprecipitation-plus-sequencing experiments, they determined that this sex swap was due to altered expression of a Y chromosome gene Sry — known for its vital role in male development — as a consequence of persistent methylation at H3K9 marks normally regulated by the Jmjd1a demethylase.

"The discovery of the critical role of chromatin modification on Sry regulation not only provides new insights into the earliest steps of mammalian sex determination," Kyoto University's Makoto Tachibana and RIKEN researcher Yoichi Shinkai, co-corresponding authors on the study, and their colleagues concluded, "but also demonstrates the importance of epigenetic regulation in spatiotemporal gene regulation during embryonic development."